Exon skipping without splice site mutation accounting for abnormal immunoglobulin chains in nonsecretory human myeloma

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Abstract
The proliferating plasma cells of patient COM with nonsecretory myeloma synthesized truncated 42 kDa γ1 chains made of a complete constant region but devoid of variable domain. In the absence of light chain expression, the shortened γ chains were retained intracellulary and were subsequently degraded within 12 h. COM neoplastic plasma cells contained short γ1 heavy chain transcripts in which the leader peptide exon was directly joined to the CH1 exon using the regular splice sites. However, study of the productive γ gene showed that the skipped variable exon was bounded by normal splicing signals and that the adjacent intron organization was not altered. Since this unusual splicing pattern was maintained when COM γ gene was transfected in murine plasmocytoma cells, exon skipping possibly relates to the modified structure of COM variable region. The latter showed a 2‐base pair deletion introducing a translation frameshift in the Vh region and a DNA insertion at the VH‐DJH junction consisting in a perfect duplication of the first 54 nucleotides of the recombined D JH segment. The lack of light chain production by COM cells was explained by alterations of the variable region of the rearranged χ gene leading to abnormally spliced transcripts.